John Libbey Eurotext – Hématologie

John Libbey Eurotext - Hématologie

Studies report that 40-100% of the general population are infected with cytomegalovirus (CMV), a virus associated with severe neurological conditions, such as CMV encephalitis, and which may have a role in some cases of Guillain-Barre syndrome. Das DHMF wird innerhalb der PEG als Arbeitsgemeinschaft geführt. CTLp recognition of VZV proteins made in latently infected cells, which include ORF4 and ORF62 proteins, was not maintained preferentially when compared to ORF10 protein, which has not been shown to be expressed during latency. While polymerase chain reaction (PCR) is a method useful for diagnosis of other viral CNS infections, it has no value for diagnosing HHV-6. Valtrex, Zovirax and famvir are pills that can be recommended for the treatment of oral herpes. It is more common in children and usually occurs within the first 24 months after transplant [9]. Brown ZA, Benedetti J, Watts DH, Berry S, Selke S, Ashley R, Corey L.

Of these, 45 patients were eligible for the study according to inclusion and exclusion criteria. Walk-in patients will be seen on a first come first served basis. In addition to VZV seropositivity or VZV infection prior to HCT, other factors associated with a higher incidence of VZV reactivation include age greater than or equal to 10 years, pretransplantation radiation with total body irradiation (TBI) or total lymphoid irradiation (TLI), graft-versus-host disease (GVHD), use of post-transplantation antithymocyte globulin, an underlying diagnosis other than chronic myelogenous leukemia and the use of cord blood [9, 12]. While the diagnosis of VZV remains mostly a clinical diagnosis, polymerase chain reaction (PCR) of skin lesions, direct fluorescent antibody of skin lesions, viral culture, serologic testing, and bronchoalveolar lavage, and CSF fluid can be used as confirmatory tests in atypical cases [13-15]. Herpes simplex type 1 typically causes cold sores or blisters around the mouth but can be transmitted to the genital area by way of oral sex (oral to genital contact). If seropositive, acyclovir is routinely used for long term prophylaxis up to one year post-transplant as this regimen has been highly effective in reducing VZV reactivation [16-18]. The optimal length of time for prophylaxis beyond one year remains undefined.

While some studies have found that the risk of VZV reactivation persists even with acyclovir use [19], others have argued that long-term prophylaxis of low dose acyclovir successfully prevented severe VZV-related symptoms and death and a significantly decreased incidence of VZV reactivation [20]. Varicella zoster immunoglobulin (VZIG) is administered to VZV seronegative post-HCT patients who are exposed to a close contact or household member with shingles or chickenpox [16]. Although there continues to be discussion about the length of prophylaxis in VZV-seropositive patients, intravenous acyclovir remains the mainstay of treatment in VZV infections and should be used for at least two days after all lesions have crusted [16]. Sprinkling baking soda or cornstarch on the sores and ulcers caused by syphilis and genital herpes can decrease the inflammation and itching. High dose valacyclovir has also been used as an alternative to acyclovir in the treatment of VZV infections [22]. Pediatr Infect Dis J 1987;6:1057–61. Prior to acyclovir prophylaxis, HSV reactivation occurred up 80% of seropositive adults and 30% of seropositive children following transplant [23, 24].

Risks for reactivation include age greater than 35 year, females, unrelated donor or cord blood grafts and GVHD [25]. Manifestations of HSV vary but localized mucocutaneous lesions in the orofacial or genital area are the most common presentation. Herpetic esophagitis occurs in 10% of patients [26]. Ice cubes, crushed and wrapped in a clear plastic bag and put on sores and inflamed genitals will bring instant rest from pain in the case of genital herpes and warts. PCR remains the preferred test to diagnose HSV infections as it is the most sensitive and specific. Viral culture, immunofluorescence assay, Tzanck smear of skin scrapings, and serology are other methods of confirming HSV infection [26]. Routine surveillance of HSV reactivation via viral culture or PCR is not routinely recommended [26].

Patients are tested for serum anti-HSV IgG prior to transplant. To prevent reactivation, seropositive allogeneic patients are given prophylaxis with acyclovir until engraftment occurs or until mucositis resolves whichever is longer [16]. The herpes virus will attach to glass, or cutlery while eating and drinking, to a towel, toothbrush or can be carried on hands. Seronegative patients are usually not given acyclovir prophylaxis even when the donor is HSV positive [16]. Patients who are on cytomegalovirus (CMV) re-activation management do not need additional acyclovir prophylaxis given ganciclovir’s or foscarnet in vitro activity against HSV 1 and 2 [16]. Valacyclovir and famciclovir are two additional antiviral agents that have also been shown to provide adequate prophylaxis to HSV in the limited studies [26]. Intravenous acyclovir is the treatment of choice for severe mucocutaneous or visceral HSV infection with higher doses recommended for HSV pneumonia, meningitis, or encephalitis.

Acyclovir is associated with shortened course of viral shedding and faster healing of lesions [27]. Oral acyclovir, famciclovir, or valacyclovir can be used for less serious HSV infections [26]. When HSV infections are unresponsive to therapy, resistance testing should be considered because 10% of HSV infections are acyclovir resistant [28]. Foscarnet and cidofovir are used for multi-drug resistant HSV but these drugs must be administered with adequate hydration given their nephrotoxicity [26]. Epstein-Barr virus (EBV) is a gamma herpes virus affecting over 90% of the world’s population, with the potential to cause uncontrollable B cell proliferation in humans [29]. It can manifest itself in post-HCT patients as primary infection or reactivation. Primary infections occur mainly in children in the form of mononucleosis, chronic active EBV infection, X-linked lymphoproliferative syndrome, and hemophagocytic lymphohistiocytosis (HLH).

EBV reactivation is often subclinical, requiring no treatment, but can present in a multitude of clinical syndromes including encephalitis/myelitis, pneumonia, hepatitis, and post-transplant lymphoproliferative disorder (PTLD). The incidence of EBV-related PTLD is less than 2% but may be as high as 20% in patients with risk factors such as HLA-mismatch or unrelated donor, T cell depletion, severe GVHD, use of anti-T cell antibodies, umbilical cord transplants, haplo identical transplants, and the use of an EBV positive donor to an EBV negative recipient [30-34]. Mortality of untreated PTLD can be as high as 84% [35]. Testing for the presence of serum anti-EBV IgG antibodies in both HCT donors and candidates can help determine the risk of primary EBV infection [16]. Recent guidelines from the European Conference in Infections in Leukemia recommend patients at high risk for PTLD who are EBV-PCR negative undergo weekly screening for EBV DNA from the day of transplant to at least 3 months afterwards [26]. Longer monitoring is recommended for patients who have undergone mismatched, unrelated, T-depleted or haplo-HCT, and who experienced early EBV reactivation, or have GVHD [36]. A surveillance strategy for EBV reactivation by viral load monitoring is recommended for high-risk HCT recipients [26, 37].

John Libbey Eurotext - Hématologie
Even though there is no defined viral load to define the diagnosis of PTLD or EBV reactivation, a rapid rise of viral load has been associated with the development of PTLD [38, 39]. Definitive diagnosis of PTLD requires the examination of biopsied tissue with immunohistochemistry or in situ hybridization in the appropriate clinical setting [39]. The initiation of preemptive therapy, defined as treatment given to an asymptomatic patient with EBV viremia, used to be a point of debate. Preemptive treatment generally reserved for high risk patients, such as those with X-linked lymphoproliferative disease, Wiskott-Aldrich syndrome, or undergoing treatment for rejection or GVHD [40]. The 4th European Conference in Infections in Leukemia (ECIL 4) recommends preemptive treatment with rituximab. Reduction of immunosuppressive agents, infusion of donor EBV-specific cytotoxic T-cell lymphocytes (CTL), and administration of cytotoxic T cell therapy are other options for preemptive therapy. There is limited data regarding EBV prophylaxis.

Antivirals such as ganciclovir, foscarnet and cidofovir have no effect on the prevention of PTLD. Immunoglobulin is not effective as a single agent in patients for prevention of EBV reactivation or infection [26]. First line treatment for PTLD is rituximab and reduction of immunosuppressive therapy although the latter is not always possible. The response rate to rituximab therapy is about 63% [41]. Rituximab has also been shown to prevent PTLD when used as preemptive therapy [41]. Infusions with EBV specific CTL have also been used for the prophylaxis and treatment of PTLD with good efficacy. However, there is a theoretical higher risk of GVHD following the therapy and the process of generating CTLs takes 8-10 weeks [42].

Response to treatment is defined as decrease in EBV-DNA load of at least 1 log of magnitude in the first week of treatment. Chemotherapy and hydroxyurea are considered second line therapy for PTLD [26]. Human herpes virus 6 (HHV-6) reactivation is common among pediatric and adult HCT recipients and 40-60% of all patients experience reactivation 2-4 weeks following transplant [43]. Clinical manifestations of HHV-6 reactivation include hepatitis, fever, rash, pneumonitis, gastroduodenitis, myleosuppression and delayed engraftment, and encephalitis. While encephalitis is uncommon, occurring at 1-8% [44-46], it can be associated with high HHV-6 viral loads, poor neurologic outcomes and increased mortality [45, 47] and is considered the most significant clinical manifestation of HHV-6 disease. Risk factors for reactivation include allogeneic HCT, sex mismatch between donor and recipient, younger age, treatment with corticosteroids, advanced hematologic malignancy, myleoablative conditioning regimen, and use of cord blood [43, 47-51]. Diagnosis of HHV-6 infection is detection of virus by quantitative PCR in the plasma or CSF [47].

However, the virus can be chromosomally integrated and resulting in high viral load in the blood and sera without disease manifestations and produce false positives [52]. There are currently no guidelines for routine surveillance of viremia or prophylaxis [16]. While viremia can often resolve without treatment, foscarnet and gancyclovir, either alone or in combination, are recommended by International Herpes Management Forum as first line therapy for HHV-6 encephalitis given its associated high morbidity and mortality [53, 54]. Cidofovir can also be used but is considered second line therapy [54]. In general, treatments with gancyclovir, cidofovir, and foscarnet have been shown to be effective in most studies [51, 55, 56]. Antiviral treatment response was observed in 89% of the patients and was shown to shorten the duration of HHV-6 reactivation in one trial [51]. Only one study showed no significant change in survival; however, the study may have been underpowered to detect a clinical significance [46].

Adenovirus can occur in HCT recipients as primary infection or reactivation of latent virus. It is more common in the pediatric population with an incidence rate of 31-47%. The frequency ranges from 3-29% in adult population [57-62]. In healthy individuals, adenovirus causes mild respiratory and gastrointestinal illness. However, in immunocompromised HCT recipients, infection by adenovirus can lead to severe respiratory disease such as pneumonia, hepatitis, colitis, hemorrhagic cystitis and enteritis, nephritis, encephalitis, keratoconjunctivitis, and disseminated disease involving multiple organ failure [63]. Disseminated disease is associated with a mortality of 8-26% [63]. Patients considered highest risk are those who have refractory GVHD, umbilical cord blood transplantation, haploidentical transplantation, stem cell graft T-cell depletion of greater than 2-3 log10, and use of anti-T cell antibodies such as antithymocyte globulin (ATG) or alemtuzumab [64, 65].

PCR of adenoviral load in peripheral blood is the preferred diagnostic test as it is the fastest and most sensitive test compared to viral culture and direct fluorescence assay [66, 67]. Adenovirus can also be detected in stool and nasal washings via PCR and the presence of virus in local sites often precedes invasive viremia by up to 11 days [68]. It is recommended to consider ophthalmology consult to screen for keratoconjunctivitis as well as gastroenterology consult for endoscopy with biopsies for diarrhea [63]. Weekly PCR monitoring for the first 6 months following HCT or the duration of severe immunosuppression can be considered for high-risk patients [63]. There is some controversy regarding the timing of initiation of treatment. Lindemans, et al [63], suggests starting preemptive treatment for high risk patient with a viral load of greater than 100cp/ml. This may be based on studies which demonstrate increased morbidity and mortality with high viral loads of adenovirus [69].

Treatment of adenovirus ranges from antiviral therapy to immunotherapy. Cidofovir is the most efficacious agent [63]. It is co-administered with probenecid and generous hydration to decrease nephrotoxicity. Ribavirin is also used but with varying effect as in-vitro adenovirus activity differs widely between subtypes [63]. Most recently, CMX001, a lipid-conjugate of the nucleotide analog, cidofovir, was shown to eradicate disseminated adenovirus infection in a HCT recipient [70]. While antivirals have some efficacy, viral clearance occurs when T cells reconstitute after HCT [63]. Adenovirus-specific cytotoxic T cells have also been shown to be effective but their use is limited to certain centers [63].

Hepatitis B virus (HBV) reactivation can occur in 14-50% of patients undergoing allogeneic HCT [71-73]. Clinical manifestation of reactivated HBV ranges from asymptomatic patients with rising ALT and HBV DNA levels to hepatitis leading to fulminant liver failure. Mortality of HBV reactivation ranges from 4 to 41% [71]. The following groups of people are at risk for developing severe hepatitis B infection: 1) HBV naïve patients exposed to HBV via infected donor, blood products, or sexual contact; 2) HCT recipients with chronic HBV infection, 3) HCT recipients undergoing prolonged immune suppression who have serologic evidence of resolved or occult HBV. Additional risk factors include allogeneic HCT from unrelated donor, steroids, and GVHD [71]. Thus, current guidelines recommend that all HCT recipients and donors undergo testing for past or active HBV infection with HBV surface antigen (HBsAg), antibodies to HBV core antigen (anti-HBc), and antibodies to HBV surface antigen (anti-HBs). Donors and recipients who test positive for HBsAg and anti-HBc are tested for HBV DNA [16].

Antiviral treatment is recommended for recipients with a positive HBV DNA. Prophylactic treatment is offered to recipients with positive anti-HBc and HBsAg. Duration of treatment has not be studied but continuing treatment 6 months after cessation of immunosuppressive therapy is commonly practiced. Quarterly monitoring of anti-HBs levels is recommended. HBV DNA testing should follow if anti-HBs titers are reduced. Patients who lose anti-HBs responses with undetectable HBV DNA can receive active immunization; patients with detectable HBV DNA receive antiviral therapy [16].

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